Vitamin D3

Once thought to have been conquered, vitamin D deficiency is now recognized as an epidemic in the United States. Meanwhile, epidemiologic (population) studies suggest that vitamin D deficiency is also a problem world-wide, with greater than 50% of the global population at risk for vitamin D deficiency. In fact, it is estimated that 50,000-70,000 people in the U.S. and 30,000-35,000 people in the U.K. die prematurely from cancer each year due to insufficient vitamin D.1-6

The primary source of vitamin D for both children and adults is from sun exposure, not from diet. Vitamin D is naturally produced in the skin following exposure to sunlight. In contrast, very few foods naturally contain vitamin D (namely fatty fish, egg yolks and liver) or are fortified with vitamin D. As a result, a varying percentage of people are vitamin D deficient at any time, with this percentage being higher in the winter, among the elderly or obese, in sun-deprived individuals, in dark-skinned people (heavy melanin effectively blocks skin synthesis of vitamin D), and in populations living in more poleward regions with lower sunlight exposure. Research also indicates that sunscreen inhibits the formation of vitamin D in the skin, even with extensive sun exposure. A sunscreen with a sun protection factor (SPF) of only 8 reduces the skin’s production of vitamin D by 95%. Furthermore, certain medications such as bile acid sequestrants (i.e. cholestyramine and colestipol) and anticonvulsants (i.e. phenobarbital) can cause vitamin D deficiency.2,7-18

Over the past several decades, the physiological role and importance of vitamin D has dramatically expanded, with recent findings indicating an increasing range of health benefits and therapeutic applications. Today, vitamin D is not only recognized for its crucial role in promoting bone health, but also for its emerging significance in regulating immune system function, reducing the risk of infectious and chronic diseases such as cancer, and facilitating normal brain function, central and peripheral nervous system function, blood clotting and blood cell formation, cardiac activity, and optimal muscle strength. Vitamin D also appears to play an important role in glucose metabolism—the conversion of blood sugar into energy.1,6,8,9,19-31

Perhaps the most well-known function of vitamin D is to regulate calcium absorption and metabolism for bone health. To this end, vitamin D promotes intestinal absorption of calcium and phosphorous, facilitates calcium transport, and reduces urinary calcium loss in order to keep calcium in the body and spare calcium stores in the bones. Vitamin D also promotes calcium deposition in bones and is required for the proper utilization of magnesium.6,9,12,25-29,31

However, vitamin D also exerts profound effects on human immune function. Vitamin D acts as an immune system modulator, increasing the activity of macrophages (white blood cells that destroy bacteria, protozoa and tumor cells) and providing anti-inflammatory effects. For example, recent research on the immunomodulating potential of vitamin D has shown that greater vitamin D intake is associated with both a lower risk of rheumatoid arthritis, as well as significant clinical improvement in patients treated with vitamin D. In addition, vitamin D dramatically stimulates the production of anti-microbial compounds that play a crucial role in protecting the respiratory tract against infection. Evidence from a 3-year randomized, controlled trial found that 104 women given a low dose of vitamin D (800 IU per day) were 3 times less likely to report cold and flu symptoms than an equal number of those given placebo. During the last year of the trial, a higher dose of vitamin D (2000 IU per day) was found to virtually eliminate all reports of colds and flu. Furthermore, experimental studies suggest that vitamin D may lower the risk of cancer by regulating cellular proliferation and differentiation and inhibiting angiogenesis—the formation of new blood vessels that contribute to tumor growth. In a recent randomized, controlled trial, daily intake of 1100 IU of vitamin D3 during a 4-year period was shown to dramatically reduce the occurrence of non-skin cancers. Such results corroborate other evidence indicating that higher vitamin D levels are associated with lower incidences of cancer.9,25,32-38

Vitamin D3, also known as cholecalciferol, is one of two forms of vitamin D used for nutritional supplementation. Vitamin D3 is manufactured from lanolin derived from the wool fat of sheep. The other form, known as vitamin D2 or ergocalciferol, is a vegetarian form of vitamin D manufactured by the ultraviolet radiation of yeast. Vitamin D3 has been proven to be the more potent form of vitamin D in both animal and human studies. Vitamin D3 has been shown to be at least 3 times more effective than vitamin D2 at raising serum vitamin D levels in.8,39-42

Current consensus among experts is that intakes of vitamin D between 1000 and 4000 IU will lead to more healthy serum levels of vitamin D. In fact, the physiologic requirement for vitamin D may be as high as 5000 IU per day for many individuals. For example, 4000 IU of vitamin D3 daily has been shown to safely and effectively increase serum vitamin D levels to high-normal concentrations in healthy adults. Likewise, daily oral intake of 2000 to 4000 IU of vitamin D appears to be the most effective way to improve vitamin D status in patients with congestive heart failure. Current research has also shown that the actual dietary need for vitamin D during pregnancy and lactation may be as high as 6000 IU per day and that the present recommended dietary requirement of 200 IU per day is based on little, if any, scientific or clinical evidence. In truth, high doses of vitamin D3 (6400 IU per day) have been shown to safely increase circulating serum vitamin D levels in both mothers and nursing infants, thus confirming that vitamin D intake above the currently recognized upper limit is safe by a large margin. It is important to point out that the Institute of Medicine’s present Dietary Reference Intakes for vitamin D were not designed and are not effective for preventing or treating vitamin D deficiency. Instead, government agencies designed current vitamin D intake recommendations only as guidelines to prevent particular metabolic bone diseases. Recent human clinical trials have confirmed that even prolonged daily intake of 10,000 IU of vitamin D3 is a safe tolerable upper intake level that has shown no evidence of adverse effects and is likely to pose no risk of toxicity, except in those with specific health conditions causing known hypersensitivity.9,37,43-55

Vitamin D deficiency can have serious consequences on overall health and well-being, especially considering that vitamin D status has been linked to greater disease susceptibility and/or mortality (death). In fact, vitamin D deficiency has been implicated in a host of diseases. For example, research indicates that vitamin D deficiency predisposes children to respiratory infections and is also associated with a higher risk of active tuberculosis. Growing scientific evidence has also demonstrated an association between low levels of vitamin D and a greater risk of hypertension, cardiovascular disease, depression, obesity, Type 1 diabetes, osteoporosis, cancer, and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. In addition, vitamin D deficiency is increasingly being diagnosed and treated in patients with cystic fibrosis.2,4,9,10,19,21,32,34,37,56-64

Results of several clinical and epidemiologic studies indicate an excess risk of both hypertension and diabetes mellitus in individuals with low vitamin D intake. Available data also indicate that the majority of patients with congestive heart failure have insufficient serum levels of vitamin D. In addition, vitamin D deficiency in pregnant women may be an independent risk factor for preeclampsia.48,58,65,66

Vitamin D deficiency in adults can also result in secondary hyperparathyroidism, which causes a loss of bone matrix and minerals that, in turn, increases the risk of osteoporosis and fractures. A high prevalence of low vitamin D levels has been reported in a number of populations worldwide, including women being treated for osteoporosis and those with fragility fractures—a bone fracture that occurs from a fall from standing height or less. Plus, poor mineralization of newly-formed bone matrix in adult bones causes osteomalacia—a painful bone disease that is often misdiagnosed as fibromyalgia or chronic pain syndrome or simply dismissed as depression. Vitamin D deficiency also causes muscle weakness, which increases the risk of falling and fractures.2,12,67-69

In addition, vitamin D deficiency has been found to cause dull, achy non-specific musculoskeletal pain that often persists despite pharmaceutical interventions and manual treatments. Several clinical investigations have confirmed that vitamin D deficiency is especially common among individuals with musculoskeletal pain, with some patients exhibiting severely deficient serum levels or even serum levels below the level of detection. Pain can be widespread or isolated to a particular area and is most commonly reported in the low-back and lumbar spine. In one study, 81% of female patients with chronic low back pain longer than 3 months exhibited vitamin D deficiency and significantly lower serum vitamin D levels than controls. In another study involving 267 adults undergoing outpatient treatment for chronic pain, 1 in 4 patients lacked sufficient serum levels of vitamin D. Patients with vitamin D deficiency were found to need higher doses of morphine for a longer duration, with 26% requiring nearly twice the morphine dose of those with adequate vitamin D levels. Patients with vitamin D deficiency also demonstrated overall poorer health, lower levels of physical functioning, and reported using morphine nearly twice as long as those with adequate vitamin D levels. Such results are not surprising considering that vitamin D deficiency has long been associated with pain and muscle weakness, with prior studies suggesting that pain-related symptoms associated with vitamin D deficiency respond poorly to pain medications. It is important to note that vitamin D deficiency is often misdiagnosed as fibromyalgia or chronic pain syndrome. Fortunately, high-dose vitamin D supplementation has been shown to eliminate musculoskeletal pain in a high percentage of patients with vitamin D deficiency.9,12,21,25,70-74

Mounting scientific evidence has implicated vitamin D deficiency with an increased risk of several deadly cancers. For example, epidemiologic evidence has demonstrated an inverse relationship between prostate cancer and serum vitamin D levels, suggesting that vitamin D deficiency increases the risk of prostate cancer. Likewise, observational studies indicate that inadequate vitamin D is associated with high incidence and mortality rates of breast cancer. According to the pooled analysis of two studies involving 1760 individuals, those with sufficient serum vitamin D levels (corresponding to a daily intake of 4000 IU) demonstrated a 50% lower risk of breast cancer than those with serum vitamin D deficiency. In addition, inadequate vitamin D is also associated with high incidence rates of colorectal cancer. Individuals with sufficient serum vitamin D levels or with a daily oral intake of 1000-2000 IU vitamin D3 exhibited a 50% lower incidence of colorectal cancer. Death from colorectal cancer has also been shown to be inversely related to serum vitamin D levels, with high serum levels associated with a 72% less risk of death compared with lower serum levels. Furthermore, higher vitamin D indices in men with early stage non-small cell lung cancer have been correlated with higher survival rates than those with lower vitamin D indices. Higher intakes of vitamin D have also been associated with lower risks for pancreatic cancer in both men and women.1,2,6,9,19,25,75-84

Vitamin D deficiency is also a common finding among patients with inflammatory and autoimmune diseases, such as ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis. For example, research has shown that multiple sclerosis is more prevalent where environmental supplies of vitamin D are lowest (i.e. more poleward regions). Another study confirmed that patients with multiple sclerosis had significantly lower serum vitamin D levels compared to healthy controls. Likewise, patients with SLE demonstrate multiple risk factors for vitamin D deficiency, with the severity of disease correlated with lower serum vitamin D levels.33,35,85-87

Furthermore, epidemiologic studies show that higher vitamin D intake by pregnant mothers reduces asthma risk by as much as 40% in children 3 to 5 years old. However, according to a recent study in The Journal of Nutrition, pregnant women and newborns living in the northern U.S. are at high risk of having insufficient vitamin D levels, including mothers taking prenatal vitamins. In fact, another study found that the amount of vitamin D commonly provided in prenatal vitamins failed to maintain adequate maternal serum vitamin D levels, and thus supplied only extremely limited amounts of vitamin D to nursing infants via breast milk. The results of these studies indicate that higher-dose supplementation is needed to improve maternal and newborn vitamin D nutritional status. Maintaining sufficient vitamin D levels is especially important for pregnant women, since vitamin D deficiency in utero and during the first year of life is associated with a higher incidence of Type 1 diabetes. Fortunately, a study of over 10,000 infants (less than 12 months of age) who received 2,000 IU of dietary vitamin D daily showed an 80% reduction in the incidence of Type 1 diabetes, with no evidence of adverse effects.50,62,88-90